Compounds having fluorine have been attracting attention in various fields such as the medical field and the field of electronic materials since the unique property derived from fluorine atom leads to exhibition of various useful functions, and the compounds have numerous applications. Therefore, various methods of effectively introducing fluorine atom into substrates have been studied. Examples of the widely known methods include the method of direct fluorination described in Japanese Patent Application Laid-Open No. Showa 53(1978)-1827; the so-called method of halogen exchange described in Yuki Gosei Kagaku (Organic Synthetic Chemistry), volume 47, page 258 (1999), in which a halogen atom in a compound having the halogen atom is exchanged with fluorine atom using HF or an alkali metal salt of fluorine such as KF; the method using hydrogen fluoride and a base such as pyridine and triethylamine; the method using a hypervalent iodine such as IF5; the method using a specific fluorinating agent such as SF4, DAST and a fluoroalkylamine, examples of which include the Yarovenko reagent; and the method of electrolytic fluorination (Chemistry of Organic Fluorine Compounds II, Monograph, American Chemical Society, 1995, page 187).
However, among the conventional methods, the methods of fluorination using fluorine gas, SF4 or DAST have a great problem with respect to safety of the reaction. The method using a nucleophilic fluorinating agent which can introduce fluorine atom conveniently and safely such as a combination of HF and a base is frequently conducted in early stages of research and development since distillation is made possible by adjusting the number of the HF molecule coordinated to the base, and glass wares can be used without the possibility of corrosion. This method is described in references (Journal fur practische Chemie Chemiker-Zeitung, 338 (1996), pages 99 to 113; G. A. Olah, Synthetic Fluorine Chemistry, chapter 8, 1992, John Wiley).
Examples of the method using a nucleophilic fluorinating agent include fluorination of sugars by the halogen-fluorine exchange such as the halogen-fluorine exchange of a compound having a halogen atom activated by carbonyl group at the α-position, the halogen-fluorine exchange of trichloropyrimidine and the halogen-fluorine exchange of a sugar triflate; synthesis of fluoroethanols by ring-opening fluorination of oxirane compounds (formation of a fluorohydrin); formation of halofluoro group or fluorosulfenyl group in unsaturated compounds; synthesis of fluorobenzene by fluorination accompanied with removal of diazo group; gem-difluorination of 1,3-dithiolanes and hydrazones; and the reaction of removing protective group of silyl ethers.
However, although the easy formation of free HF can be suppressed so that the safety of the complex compound of HF and a base is enhanced, drawbacks arise in that the formation of the fluorine anion having the nucleophilicity becomes difficult, and the reactivity is small. Therefore, severe reaction conditions are necessary to obtain an excellent result of the reaction, and it is often difficult that the desired reaction proceeds. Moreover, from the standpoint of the industrial application, improvement is necessary for completing the reaction at a low temperature in a short time so that the energy cost is reduced.
It is the actual situation that the other fluorinating agents are expensive and cannot be handled easily. Among the above methods, the method of using a specific compound having fluorine atom as the fluorinating agent is frequently used in the early stage of research and development on drugs and functional materials since fluorine atom can be introduced relatively easily. However, as described above, the conventional technology of fluorination is not satisfactory for making the desired fluorination proceed selectively, efficiently and safely.
Recently, various attempts have been made to improve the selectivity and the activity of the reaction. Examples of the attempt include the acceleration of the reaction using microwave. Since microwave does not have energy sufficient for starting a reaction, the application of microwave to chemical reactions is heretofore rarely conducted. Recently, a study showing that the activity and the selectivity of a reaction is improved by irradiation with microwave has been reported. This report is attracting attention since the result cannot be explained by the simple acceleration of the reaction by heating (Journal of Physical Organic Chemistry, 2000 (13), 579-586). However, the attempts on the application of microwave to the fluorination are scarce. For example, no reports can be found except the application to the Schieman reaction (Japanese Patent Application (as a national phase under PCT) Laid-Open No. Heisei 12(2000)-59384).
As for saccharides, a wide range of application and development are expected since saccharides play important roles in the activities of the life such as the communication between cells and the mechanism of immunity as the energy source and as the sugar chain in proteins and have the ability of forming organs such as skins and bones. For example, chitosan, which is a high order condensate having a repeating unit of glucosamine and is produced by hydrolysis or fermentation of crustaceans or glucose as the material, is used as an additive, an antiseptic or a pet food in the field of foods and as an artificial skin, a stitching thread, a membrane for artificial dialysis and a film for controlled release in the field of medical treatments. Chitosan is also used in the field of the drug as an anticancer agent, an immunostimulator, an agent for suppressing blood glucose elevation and an agent for suppressing cholesterol absorption, in the field of the agriculture as an agent for soil amelioration, an antivirus agent and an insecticide, in the field of industry as soap, a hair tonic, a cosmetic and a tooth paste, and in the field of the environment as an agent for trapping waste fluids and an agent for treating heavy metals and waste water.
As described above, as the application of saccharides, the development of products having useful functions in the fields of foods, drugs, medical treatments, agriculture, industry and environment is promoted by bonding specific monosaccharides in higher orders or by introducing amino group, acetyl group or fluorine atom into saccharides.
In particular, fluorinated sugars obtained by fluorinating saccharides exhibiting excellent adaptability to the human body are actively studied for application as the anticancer agent and an immunosuppressant. Examples of the method of fluorination used for this purpose include the direct fluorination with the fluorine gas, the method of halogen-fluorine exchange, the method using hydrogen fluoride and a base such as pyridine and triethylamine, and the method using a fluorinating agent such as IF5, SF4, DAST and the Yarovenko reagent.
However, the introduction of fluorine atom into a specific position of a saccharide is often difficult since a saccharide has a plurality of active groups such as hydroxyl groups. For example, it is known that, when methyl 2,3-0-isopropylidene-β-D-ribofuranoside is fluorinated with DAST, 2,3-0-isopropylidene-5-0-methyl-β-D-ribofuranosyl fluoride which is a product of rearrangement is obtained, but the fluorination of hydroxyl group as the object reaction does not proceed. It is also known that the object reaction does not proceed when the combination of HF and a base which is a convenient fluorinating agent such as the HF-pyridine complex compound and the HF-triethylamine complex compound is used. When an agent having a greater acidity is used to promote the reaction, side reactions such as scission of the protective group take place.
When fluorine gas having a greater reactivity is used, the selective introduction of fluorine is impossible. To obtain the object compound, it is necessary that the halogenation be conducted using another halogen having a smaller reactivity, and then the halogen-fluorine exchange be conducted.
As described above, it is very difficult that a specific position of a saccharide is easily fluorinated without affecting the protective group in accordance with the conventional technology.
The present invention has an object of overcoming the above problems and providing a method of making the fluorination of a desired substrate proceed highly selectively, efficiently and safely, and to provide a method of fluorinating a specific position of a saccharide selectively without affecting a protective group at a temperature within a wide range safely and easily.